GPR120, a G protein-coupled receptor, causes intracellular signaling through binding with unsaturated long chain fatty acid, such as alpha-linoleic acid, to induce various biological reactions. Actions of GPR120 and its ligand have been reported to promote secretion of GLP-1 (glucagon-like-peptide-1) having the function of reducing a blood glucose level in the gastrointestinal cell lines. (see Nature Medicine, vol. 11, No. 1, January 2005, pp. 90-94). GLP-1, which is a peptide hormone released from L cells which are enteroendocrine cells present in the ileum, the large intestine and the like, has been found to induce insulin secretion depending on a blood glucose level. Accordingly, compounds having the action of promoting GLP-1 secretion are expected as agents for treating diabetes mellitus that allow avoidance of the risk of hypoglycemia due to drug overdosage. GLP-1 is also suggested to be efficacious for delaying the apoptosis of beta cells in type II diabetes mellitus or prolonging the efficacy of islet cell transplantation against type I diabetes mellitus because of having the action of inducing pancreatic beta-cell growth and differentiation from stem cells. GPR120 is known to be also expressed in adipocytes. GPR120 has been found to be increasingly expressed by adipose differentiation induction. In addition, actions of GPR120 and its ligand have been reported to suppress lipolysis in adipose-differentiated cells. A high blood lipid level is known to be one of the causes of insulin resistance. Suppression of lipolysis by a GPR120 agonist is thus expected to decrease the level of free fatty acid in blood to normalize a blood lipid level, resulting in improvement in insulin resistance. Furthermore, GPR120 is also expressed in the pituitary gland, and a GPR120 ligand is reported to suppress adrenocorticotropic hormone secretion. Adrenocorticotropic hormone promotes glucocorticoid secretion downstream thereof to induce action such as promotion of glyconeogenesis in the liver, inhibitory action against glucose uptake in muscle and peripheral tissue, lipolysis in adipose tissue or release of fatty acid or glycerol. Accordingly, GPR120 is considered to exhibit hypoglycemic action or blood lipid lowering action via suppression action against adrenocorticotropic hormone secretion even in the center. In light of the above description, a compound having GPR120 agonist activity is considered to be extremely useful as an agent for treating and/or preventing diabetes mellitus, obesity and hyperlipidemia.
Compounds related structurally to a compound according to an embodiment of the present invention include, e.g., a compound represented by the following formula:
which is described (see US 20080108659). The compound in accordance with US 20080108659 has cyano on the benzene ring of isoindolin-1-one, whereas a compound according to an embodiment of the present invention has no cyano group. In addition, the compound according to an embodiment of the present invention always has oxo on cycloalkyl, which is composed of carbon atoms of which one may be substituted with a nitrogen atom, whereas the compound in accordance with US 20080108659 has no oxo group. Furthermore, use of the compound according to US 20080108659 is treatment of cancer, but it is not disclosed or suggested that the compound according to US 20080108659 is useful in treatment and/or prevention of diabetes, obesity and hyperlipidemia.
A compound represented by the following formula:
is also described (see WO 2005037789). Although the compound has a phthalimide backbone, cyclohexyl in the compound has no oxo group whereas cycloalkyl in a compound according to an embodiment of the present invention always has oxo. In addition, the compound according to WO 2005037789 is used for a herbicide, but it is not disclosed or suggested that the compound according to WO 2005037789 is useful in treatment and/or prevention of diabetes, obesity and hyperlipidemia.
Compounds having isoindolin-1-one skeleton are described in WO 2002081447 and WO 199842666. In the compounds, cycloalkyl has no oxo group. A substituent on a benzene ring constituting isoindolin-1-one skeleton is different from that of the compound according to an embodiment of the present invention. In addition, use in accordance with WO 2002081447 and WO 199842666 relates to inflammatory diseases/autoimmune diseases, but WO 2002081447 and WO 199842666 do not disclose or suggest that the compounds are useful in treatment and/or prevention of diabetes, obesity and hyperlipidemia.
A compound represented by the following formula:
or the like is also described (see U.S. Pat. No. 4,964,895). The compound according to U.S. Pat. No. 4,964,895 inevitably contains a nitro group in a para position of a phenyl group constituting phenoxypyrazole whereas a compound according to an embodiment of the present invention has no nitro group. In addition, the compound is used for a herbicide, but it is not disclosed or suggested that the compound is useful in treatment and/or prevention of diabetes, obesity and hyperlipidemia.
A compound represented by the following formula:
or the like is also described (see Egyptian Journal of Pharmaceutical Sciences, vol. 21, pp. 177-187, 1982). From such compounds, containing piperidinyl having no oxo group, a compound according to an embodiment of the present invention differs in its inevitably having an oxo group in case of containing cycloalkyl, piperidinyl, etc. In addition, such compounds always have a hydroxy group on a phenyl group whereas the compound according to an embodiment of the present invention has no hydroxy group on a phenyl group bound to a nitrogen atom of a phthalimido group. Furthermore, the document, Egyptian Journal of Pharmaceutical Sciences, vol. 21, pp. 177-187, 1982, describes that the compound according thereto is useful as an antimalarial drug, but does not disclose or suggest that the compound is useful in treatment and/or prevention of diabetes, obesity and hyperlipidemia.